The IκB kinase inhibitor ACHP strongly attenuates TGFβ1‐induced myofibroblast formation and collagen synthesis

Abstract

Excessive accumulation of a collagen‐rich extracellular matrix (ECM) by myofibroblasts is a characteristic feature of fibrosis, a pathological state leading to serious organ dysfunction. Transforming growth factor beta1 (TGFβ1) is a strong inducer of myofibroblast formation and subsequent collagen production. Currently, there are no remedies for the treatment of fibrosis. Activation of the nuclear factor kappa B (NF‐κB) pathway by phosphorylating IκB with the enzyme IκB kinase (IKK) plays a major role in the induction of fibrosis. ACHP {2‐Amino‐6‐[2‐(cyclopropylmethoxy)‐6‐hydroxyphenyl]‐4‐(4‐piperidinyl)‐3 pyridinecarbonitrile}, a selective inhibitor of IKK, prohibits the activation of the NF‐κB pathway. It is not known whether ACHP has potential anti‐fibrotic properties. Using adult human dermal and lung fibroblasts we have investigated whether ACHP has the ability to inhibit the TGFβ1‐induced transition of fibroblasts into myofibroblasts and its excessive synthesis of ECM. The presence of ACHP strongly suppressed the induction of the myofibroblast markers alpha‐smooth muscle actin (αSMA) and SM22α, as well as the deposition of the ECM components collagen type I and fibronectin. Furthermore, post‐treatment with ACHP partly reversed the expression of αSMA and collagen type I production. Finally, ACHP suppressed the expression of the three collagen‐modifying enzymes lysyl hydroxylase (PLOD1,PLOD2 and PLOD3) in dermal fibroblasts, but did not do so in lung fibroblasts. We conclude that the IKK inhibitor ACHP has potent antifibrotic properties, and that the NF‐κB pathway plays an important role in myofibroblast biology.

The calcium channel proteins ORAI3 and STIM1 mediate TGF-β inducedSnai1expression

“…However, when used in combination with TGF-β treatment, or with 2APB+TGF-β, there was a significant decrease in Snai1 expression (Figure 3A ), suggesting that the AKT pathway is required for TGF-β dependent Snai1 transcription. Similar results were observed when the cells were treated with the inhibitor ACHP [ 39 ], which interferes with the DNA binding ability of NF-κB (Figure 3B ).…”

“…After serum starvation, the cells were treated with 2APB for 24 hours. At 18 hours, the cells were treated with 50 uM of the NFKB inhibitor ACHP for a 4-hour pretreatment as previously published [ 39 ] before addition of TGF-β at 22 hours. For the AKT1/2 inhibitor, NMuMG cells were treated with 10 uM of the inhibitor at 20 hours for a 2-hour pretreatment as described previously [ 38 ] before the TGF-β treatment at 22 hours for 2 hours.…”

Inhibition of IκB Kinase at 24 Hours After Acute Kidney Injury Improves Recovery of Renal Function and Attenuates Fibrosis

“…We have discovered that inhibition of IKK at 24 hours after IRI abolishes the formation of myofibroblasts seen in vehicle‐treated animals at 7 days after IRI. The finding that inhibition of IKK attenuates myofibroblast formation and collagen I production caused by TGF‐β in dermal fibroblasts in vitro supports the view that activation of IKK is a key driver of the phenotypic change caused by TGF‐β in fibroblasts and potentially other cells.…”

Roles of PLODs in Collagen Synthesis and Cancer Progression

“…ACHP (2-Amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(4-piperidinyl)−3 pyridinecarbonitrile), a selective inhibitor of IκB kinase, suppresses expression of all three PLOD genes in dermal fibroblasts, but not in lung fibroblasts (Mia and Bank, 2015 ). Therefore, activation of NF-kB pathway may induce PLOD expression in certain types of cells.…”